The avermectins are a family of macrocyclic lactones originally isolated from the actinomycete Streptomyces avermitilis. The semisynthetic avermectin derivative, ivermectin (22,23-dihydroavermectin B.sub.1a), is used throughout the world to treat parasitic helminths and insect pests of man and animals. Discovered some 15 years ago, the avermectins remain the most potent broad spectrum endectocides exhibiting low toxicity to the host. Avermectins exhibit an essentially irreversible interaction with a high affinity site in nematode [Schaeffer, J. M. & Haines, H. W. Biochem. Pharm. 38, 2329-2338 (1989); Cully, D. F. & Paress P. S., Molecular Pharm. 40:326-332 (1991)] and insect [Rohrer, S. P., Meinke, P. T., Hayes, E. C., Mrozik, H. & Schaeffer, J. M. Proc. Natl. Acad. Sci, 89, 4168-4172 (1992)] membranes and induce an increase in membrane chloride permeability in nematodes [Martin, R. J. & Pennington, A. J. Br. J. Pharmacol. 98, 747-756 (1989)], arthropods [Scott, R. H. & Duce, I. R. Pestic. Sci. 16, 599-604 (1985 )], [Duce, I. R. & Scott, R. H. Brit. J. Pharmacol. 85, 395-401 (1985)] and crustaceans [Zufall, F., Franke, C. & Hatt, H. J. Exp. Biol. 142, 191-205 (1989)]. The natural ligand of the avermectin-sensitive chloride channel remains unclear [Turner, M. J. & Schaeffer, J. M. Ivermectin and Abamectin (eds. Campbell, W. C.) 73-88 (Springer-Verlag, New York, 1989)]. Glutamate-gated chloride channels, or H-receptors, have been identified in arthropod nerve and muscle [Lingle, C. & Marder, E. Brain Res. 212, 481-488 (1981)], [Horseman, B. G., Seymour, C., Bermudez, I. & Beadle, D. J. Neurosci. Lett. 85, 65-70 (1988)], [Wafford, K. A. & Sattelle, D. B. J. Exp. Bio. 144, 449-462 (1989)], [Lea, T. J. & Usherwood, P. N. R. Comp. Gen. Parmacol. 4, 333-350 (1973)], [Cull-Candy, S. G. J. Physiol. 255, 449-464 (1976)]. It has been proposed that avermectins activate glutamate-gated chloride channels on locust muscle [Scott, R. H. & Duce, I. R. Pestle, Sci. 16, 599-604 (1985)].
The soil nematode Caenorhabditis elegans is very sensitive to the avermectins and is used as an in vitro model to examine the efficacy of different anthelminthic compounds [Schaeffer, J. M. & Haines, H. W. Biochem. Pharm. 38, 2329-2338 (1989)]. Xenopus laevis oocytes injected with C. elegans poly (A).sup.+ RNA express an avermectin-sensitive chloride channel [Arena, J. P., Liu, K. K., Paress, P. S. & Cully, D. F. Mol. Pharmacol. 40, 368-374 (1991 )]. It has been established that this channel is also sensitive to glutamate [Arena, J. P., Liu, K. K., Paress, P. S., Schaeffer, J. M. & Cully, D. F. Mol. Brain Res. 15, 339-348 (1992)]. Similar to the H-receptors from locust muscle, the glutamate- and avermectin-sensitive current is activated by ibotenate and blocked with low affinity by picrotoxin [Scott, R. H. & Duce, I. R. Pestic, Sci. 16, 599-604 (1985)], [Lea, T. J. & Usherwood, P. N. R. Comp. Gen. Pharmacol. 4, 333- 350 (1973)], [Cull-Candy, S. G. J. Physiol. 255, 449-464 (1976)], [Arena, J. P., Liu, K. K., Paress, P. S., Schaeffer, J. M. & Cully, D. F. Mol. Brain Res. 15, 339-348 (1992)].